Congestive heart failure is a complex clinical syndrome characterized by diminished cardiac contractile function and decreased exercise tolerance. Despite advances in medical therapy, 40% of patients die within one year of diagnosis and 70% are dead at five years.
A number of clinical predictors of survival in heart failure have been identified including age, decreased cardiac output and high blood pressure. However, clinical parameters alone have been of limited value in predicting survival in patients with congestive heart failure. It also appears that the genetic background of the individual plays a role. Accordingly, there is a need to identify genetic markers which are associated with improved or decreased survival in patients with heart failure.
The adenosine monophosphate deaminase 1 (AMPD1) gene is the predominant member of the AMPD multi-gene family expressed in adult cardiac myocytes and adult skeletal muscle. Approximately 20% of Caucasians and African Americans are heterozygous for a single mutant allele, AMPD1(+/-), which specifies a nonsense mutation in the second coding exon of this gene. This mutation leads to premature peptide chain termination and production of truncated peptide which is catalytically inactive. Deficiency in this enzymatic activity in myocytes resulting from the AMPD1 (+/-) genotype may have one of several metabolic consequences. A marked decrease in AMPD1 activity in myocytes may lower the adenylate energy charge in the myocyte by limiting deamination of AMP. A partial reduction in the activity of this enzyme may cause the myocyte to produce more adenosine following ATP catabolism. Increased adenosine production may be beneficial as adenosine is known to have potent cardioprotective effects. In patients with congestive heart failure, the residual cardiac myocytes experience greater metabolic demands; therefore, a reduction in AMPD activity may lead to increased adenosine production which could improve cardiac function.
Accordingly, compositions and methods which inhibit AMPD activity are desired. Further, methods of identifying patients who are likely to develop congestive heart failure and identifying those who may benefit from a cardiac transplant are also desired.